Method for treating Alzheimer&#39;s disease

ABSTRACT

A method of treating amyloid diseases by administering a compound of Formula I:                    
     wherein: 
     R 7 -R 13  are independently —H or —OH; and 
     A is H, —OH, or a moiety of Formula II:                    
      wherein: 
     R 1  is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl; 
     R 2  is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl; 
     R 3  is hydrogen or lower alkyl of up to 6 carbon atoms; 
     R 4  is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R 4  together with R 5  can represent —CH 2 —O—; 
     X is a valency bond, —CH 2 , oxygen or sulfur; 
     Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl; 
     R 5  and R 6  are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a —CONH 2 — group, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms, lower alkysulphinyl of up to 6 carbon atoms and lower alkylsulphonyl of up to 6 carbon atoms; or 
     R 5  and R 6  together represent methylenedioxy; or a pharmaceutically acceptable salt thereof, for treating amyloid diseases, and, thus, having utility in the treatment of Alzheimer&#39;s disease.

This application claims the benefit of U.S. Provisional Application No.60/062,366 filed Oct. 15, 1997.

FIELD OF THE INVENTION

The present invention relates to a novel method for treating amyloiddiseases, in particular Alzheimer's disease, using carbazole compoundsof Formula I, preferably carvedilol or hydroxylated derivatives ofcarvedilol.

BACKGROUND OF THE INVENTION

Amyloid diseases are characterized by the presence of extracellularordered, but non-crystalline, protein aggregates comprised ofcross-β-fibril/antiparallel β-sheets formed through incorrect proteinfolding. Amyloid is usually pathogenic. The most common clinicalamyloidoses are Alzheimer's disease, chronic inflammation, multiplemyelomas, Type II diabetes and Creutzfeldt-Jacob disease. Amyloiddiseases may cause cardiac problems in old age familial amyloidpolyneuropathy, and may also create the need for long-term dialysis. Ageneral amyloidosis inhibitor could be beneficial in treating amyloiddiseases, since systemic amyloid formation is reversible, and existingamyloid deposits may be resorbed, once the rate of deposition is slowedor halted.

Alzheimer's disease (AD) is the most common cause of dementia in oldage, and afflicts 5-10% of all individuals over the age of 65 years.Characteristic changes in the brain include senile plaques,neurofibrillary tangles, and the degeneration and loss of neurons.Senile plaques are located extracellularly and contain deposits offibrillar β-amyloid, the most important component of which is the βA4peptide. Aggregated forms of βA4 are toxic to cultured neurons in vitro[L. Iverson et al., Biochem. J., 311, 1-16 (1995)], and the formationand aggregation of βA4 in the brain is an essential early mediator ofthe pathology of AD.

Surprisingly, it has been found that carvedilol and related Formula Icompounds are useful for treating amyloid diseases. In particular thesecompounds are useful in inhibiting the formation of the neurotoxic βA4oligomeric aggregate, and, thus, they would be useful in the treatmentof Alzheimer's disease.

SUMMARY OF THE INVENTION

The present invention provides a new method of using compounds which aredual non-selective β-adrenoceptor and α₁-adrenoceptor antagonists, inparticular the carbazolyl-(4)-oxypropanolamine compounds of Formula I,preferably carvedilol, in the treatment of amyloid diseases.

The present invention also provides a new method of treatment usingcompounds which are dual non-selective β-adrenoceptor andα₁-adrenoceptor antagonists, in particular thecarbazolyl-(4)-oxypropanolamine compounds of Formula I, preferablycarvedilol, for inhibiting the formation of the neurotoxic βA4oligomeric aggregate, in mammals, particularly in humans. In particular,the present invention provides a method using said compounds fortreating Alzheimer's disease.

This invention further provides a method for treating Alzheimer'sdisease which comprises administering stepwise or in physicalcombination a compound of Formula I and a cognition enhancer, such asMemric.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a new method of using compounds which aredual non-selective β-adrenoceptor and α₁-adrenoceptor antagonists, inparticular the carbazolyl-(4)-oxypropanolamine compounds of Formula I,preferably carvedilol, in the treatment of amyloid diseases. Inparticular, the present invention provides a new method for inhibitingthe formation of the neurotoxic βA4 oligomeric aggregate using compoundswhich are dual non-selective β-adrenoceptor and α₁-adrenoceptorantagonists. Preferably, this invention provides a new method forinhibiting the formation of the neurotoxic βA4 oligomeric aggregate, inparticular in the treatment of Alzheimer's disease, using compounds ofFormula I:

wherein:

R₇-R₁₃ are independently —H or —OH; and

A is H, —OH, or a moiety of Formula II:

 wherein:

R₁ is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selectedfrom benzoyl and naphthoyl;

R₂ is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkylselected from benzyl, phenylethyl and phenylpropyl;

R₃ is hydrogen or lower alkyl of up to 6 carbon atoms;

R₄ is hydrogen or lower alkyl of up to 6 carbon atoms, or when X isoxygen, R₄ together with R₅ can represent —CH₂—O—;

X is a valency bond, —CH₂, oxygen or sulfur;

Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl;

R₅ and R₆ are individually selected from hydrogen, fluorine, chlorine,bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a —CONH₂— group,lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of upto 6 carbon atoms, lower alkysulphinyl of up to 6 carbon atoms and loweralkylsulphonyl of up to 6 carbon atoms; or

R₅ and R₆ together represent methylenedioxy;

or a pharmaceutically acceptable salt thereof.

More preferably, the present invention provides a new method forinhibiting the formation of the neurotoxic βA4 oligomeric aggregateusing compounds of Formula III:

wherein:

R₁ is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selectedfrom benzoyl and naphthoyl;

R₂ is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkylselected from benzyl, phenylethyl and phenylpropyl;

R₃ is hydrogen or lower alkyl of up to 6 carbon atoms;

R₄ is hydrogen or lower alkyl of up to 6 carbon atoms, or when X isoxygen, R₄ together with R₅ can represent —CH₂—O—;

X is a valency bond, —CH₂, oxygen or sulfur;

Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl;

R₅ and R₆ are individually selected from hydrogen, fluorine, chlorine,bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a —CONH₂— group,lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of upto 6 carbon atoms, lower alkysulphinyl of up to 6 carbon atoms and loweralkylsulphonyl of up to 6 carbon atoms; or

R₅ and R₆ together represent methylenedioxy;

or a pharmaceutically acceptable salt thereof. These compounds areuseful in the treatment of Alzheimer's disease.

Most preferably, the present invention provides a new method forinhibiting the formation of the neurotoxic βA4 oligomeric aggregateusing a compound of Formula IV, better known as carvedilol or(1-(carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol):

This compound is useful in the treatment of Alzheimer's disease.

Since Formula I compounds are amyloidosis inhibitors, these compoundswould be useful not only in the treatment of Alzheimer's disease, butthey would also be useful in the treatment of chronic inflammation,multiple myelomas, Type II diabetes and Creutzfeldt-Jacob disease.Additionally, the compounds of the instant invention may be useful intreating cardiac problems in old age familial amyloid polyneuropathy,and they may also prevent the need for long-term dialysis.

Formula I compounds, of which carvedilol is exemplary, are novelmultiple action drugs useful in the treatment of mild to moderatehypertension. Carvedilol is known to be both a competitive non-selectiveβ-adrenoceptor antagonist and a vasodilator, and is also a calciumchannel antagonist at higher concentrations. The vasodilatory actions ofcarvedilol result primarily from α₁-adrenoceptor blockade, whereas theβ-adrenoceptor blocking activity of the drug prevents reflex tachycardiawhen used in the treatment of hypertension. These multiple actions ofcarvedilol are responsible for the antihypertensive efficacy of the drugin animals, particularly in humans. See Willette, R. N., Sauermelch, C.F. & Ruffolo, R. R., Jr. (1990) Eur. J. Pharmacol., 176, 237-240;Nichols, A. J., Gellai, M. & Ruffolo, R. R., Jr. (1991) Fundam. Clin.Pharmacol., 5, 25-38; Ruffolo, R. R., Jr., Gellai, M., Hieble, J. P.,Willette, R. N. & Nichols, A. J. (1990) Eur. J. Clin. Pharmacol., 38,S82-S88; Ruffolo, R. R., Jr., Boyle, D. A., Venuti, R. P. & Lukas, M. A.(1991) Drugs of Today, 27, 465-492; and Yue, T.-L., Cheng, H., Lysko, P.G., Mckenna, P. J., Feuerstein, R., Gu, J., Lysko, K. A., Davis, L. L. &Feuerstein, G. (1992) J. Pharmacol. Exp. Ther., 263, 92-98.

The antihypertensive action of carvedilol is mediated primarily bydecreasing total peripheral vascular resistance without causing theconcomitant reflex changes in heart rate commonly associated with otherantihypertensive agents. Willette, R. N., et al. supra; Nichols, A. J.,et al. supra; Ruffolo, R. R., Jr., Gellai, M., Hieble, J. P., Willette,R. N. & Nichols, A. J. (1990) Eur. J. Clin. Pharmacol., 38, S82-S88.Carvedilol also markedly reduces infarct size in rat, canine and porcinemodels of acute myocardial infarction, Ruffolo, R. R., Jr., et al.,Drugs of Today, supra, possibly as a consequence of its antioxidantaction in attenuating oxygen free radical-initiated lipid peroxidation.Yue, T.-L., et al. supra.

According to the instant invention, compounds which are dualnon-selective β-adrenoceptor and α₁-adrenoceptor antagonists, inparticular the compounds of Formula I, preferably carvedilol, treatamyloid diseases. These compounds inhibit the formation of theneurotoxic βA4 oligomeric aggregate, and, therefore, said compounds areuseful for treating Alzheimer's disease.

Some of the compounds of Formula I are known to be metabolites ofcarvedilol. Certain preferred compounds of the present invention, thatis, the compounds of Formula I wherein A is the moiety of Formula IIwherein R1 is —H, R2 is —H, R3 is —H, R4 is —H, X is O, Ar is phenyl, R5is ortho —OH, and R6 is —H, and one of R₇, R₉, or R₁₀ is —OH, aremetabolites of carvedilol.

Compounds of Formula I may be conveniently prepared as described in U.S.Pat. No. 4,503,067. Reference should be made to said patent for its fulldisclosure, the entire disclosure of which is incorporated herein byreference.

Pharmaceutical compositions of the compounds of Formula I, includingcarvedilol, may be administered to patients according to the presentinvention in any medically acceptable manner, preferably orally. Forparenteral administration, the pharmaceutical composition will be in theform of a sterile injectable liquid stored in a suitable container suchas an ampoule, or in the form of an aqueous or nonaqueous liquidsuspension. The nature and composition of the pharmaceutical carrier,diluent or excipient will, of course, depend on the intended route ofadministration, for example whether by intravenous or intramuscularinjection

Pharmaceutical compositions of the compounds of Formula I for useaccording to the present invention may be formulated as solutions orlyophilized powders for parenteral administration. Powders may bereconstituted by addition of a suitable diluent or otherpharmaceutically acceptable carrier prior to use. The liquid formulationis generally a buffered, isotonic, aqueous solution. Examples ofsuitable diluents are normal isotonic saline solution, standard 5%dextrose in water or buffered sodium or ammonium acetate solution. Suchformulation is especially suitable for parenteral administration, butmay also be used for oral administration or contained in a metered doseinhaler or nebulizer for insufflation. It may be desirable to addexcipients such as ethanol, polyvinyl-pyrrolidone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride orsodium citrate.

Alternatively, these compounds may be encapsulated, tableted or preparedin a emulsion or syrup for oral administration. Pharmaceuticallyacceptable solid or liquid carriers may be added to enhance or stabilizethe composition, or to facilitate preparation of the composition. Liquidcarriers include syrup, peanut oil, olive oil, glycerin, saline,ethanol, and water. Solid carriers include starch, lactose, calciumsulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc,pectin, acacia, agar or gelatin. The carrier may also include asustained release material such as glyceryl monostearate or glyceryldistearate, alone or with a wax. The amount of solid carrier varies but,preferably, will be between about 20 mg to about 1 g per dosage unit.The pharmaceutical preparations are made following the conventionaltechniques of pharmacy involving milling, mixing, granulating, andcompressing, when necessary, for tablet forms; or milling, mixing andfilling for hard gelatin capsule forms. When a liquid carrier is used,the preparation will be in the form of a syrup, elixir, emulsion or anaqueous or non-aqueous suspension. Such a liquid formulation may beadministered directly p.o. or filled into a soft gelatin capsule.

Dosing in humans for the treatment of disease according to the presentinvention should not exceed a dosage range of from about 3.125 to about50 mg of the compounds of Formula I, particularly carvedilol, preferablygiven twice daily. As one of ordinary skill in the art will readilycomprehend, the patient should be started on a low dosage regimen of thedesired compound of Formula I, particularly carvedilol, and moniteredfor well-known symptoms of intolerance, e.g., fainting, to suchcompound. Once the patient is found to tolerate such compound, thepatient should be brought slowly and incrementally up to the maintenancedose. The choice of initial dosage most appropriate for the particularpatient is determined by the practitioner using well-known medicalprinciples, including, but not limited to, body weight. In the eventthat the patient exhibits medically acceptable tolerance of the compoundfor two weeks, the dosage is doubled at the end of the two weeks and thepatient is maintained at the new, higher dosage for two more weeks, andobserved for signs of intolerance. This course is continued until thepatient is brought to a maintenance dose.

This invention further provides a method for treating Alzheimer'sdisease which comprises administering stepwise or in physicalcombination a compound of Formula I and a cognition enhancer, such asMemric. The compound known as Memric is[R-(Z)]-(methoxyimino)-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrilemonohydrochloride. The methods for its preparation are disclosed inEP-A-0392803, WO95/31456 and WO93/17018.

The dose of Memric will vary in the usual way with the seriousness ofthe disorder, the weight of the sufferer, and the relative efficacy ofthe compound. However, as a general guide suitable daily doses below0.01 mg/g more particularly 0.003 mg/kg and below, for example0.0001-0.003 mg/kg, such as 0.00035-0.003 mg/kg, 0.0007-0.003 mg/kg,0.0001-0.0007 mg/kg or 0.00035-0.002 mg/kg. Suitable unit doses toachieve such daily doses are 5, 12.5, 25, 50 or 75 g, administered twicedaily and, in the case of 50 g, once daily.

It will be appreciated that the actual preferred dosages of thecompounds being used in the compositions of this invention will varyaccording to the particular composition formulated, the mode ofadministration, the particular site of administration and the host beingtreated.

No unacceptable toxicological effects are expected when the compounds ofFormula I are used according to the present invention.

The examples which follow are not intended to limit the scope of thisinvention, but are provided to illustrate how to use the compounds ofthis invention. Many other embodiments will be readily apparent to thoseskilled in the art.

EXPERIMENTAL

Determination of the Inhibition of Beta-Amyloid Peptide Aggregation byImmunoassay

Beta-amyloid (1-40) peptide from Bachem UK was dissolved in 0.1% aceticacid at 2 mg/ml and further diluted to 55 ug/ml in phosphate bufferedsaline (Sigma P4417) containing 0.02% Tween 20 (PBS-Tween). Candidateinhibitors were dissolved in DMSO at 10 mg/ml and further diluted inPBS-Tween. For each candidate inhibitor, 45 ul of 55 ug/ml peptidesolution was incubated with 5 ul of appropriately diluted inhibitorovernight at 37° C. in Linbro Titertek EIA II shallow well plates (ICN,EIA II Microplates, cat no. 76-181-04). Plates were sealed during allincubations with Dynatech Labs, cat # 001-010 3501 plate sealers.

For the immunoassay, plates (Gibco BRL, flat bottom 96 well plate,catalogue # 1-67008-A) were coated (overnight at 4° C.) with 2F12capture antibody, raised to beta-amyloid 1-16 peptide, at 1:3000 in PBS.After coating, antibody solution was aspirated and plates were blockedby incubating for 60 minutes at 37° C. with 1% gelatine v/v (AmershamRPN416), 2.5% goat serum v/v (Sigma G9023) in assay buffer (50 mM TrisHC, 150 mM NaCl, 0.5% bovine gamma globulins, 0.05% Tween 20, pH 7.4,passed through a 0.2 um filter before use). Following blocking, plateswere washed 4×250 ul with phosphate buffered saline with Tween 20 (SigmaCat No P3563). To assay aggregated peptide content of samples incubatedwith candidate inhibitors, samples were diluted with assay buffer and 50ul aliquots containing the equivalent of 20 ng beta amyloid 1-40 wereadded to the wells of the 2F12 coated plate. The detection antibody wasa dextran-biotin conjugated 2F12 fab fragment: this antibody was diluted1:3000 in assay buffer. The 2F12 coated plate containing beta-amyloid140 and 150 ul of detection antibody was incubated overnight at 4° C.Plates were subsequently washed (4×250 ul) with phosphate bufferedsaline with Tween 20.

Quantitation of peptide-antibody complexation was achieved by thebinding of strepatavidin-Europium. To each well was added 200 ulstreptavidin-Europium (Wallac, Catalogue # 1244-360) diluted 1:500 in0.5% BSA, 0.05% γ Globulin, 0.01% Tween 20, 20 uM DTPA (Sigma D 6518) inTris buffered saline pH 7.4. Plates were incubated at room temperaturefor 60 minutes before washing with phosphate buffered saline. Finally,200 ul of enhancer solution (Wallac, Catalogue # 1244-105) was added toeach well and the plate was shaken for 5 minutes at room temperaturebefore measurement of emission by time-resolved fluorescence on a Wallac1234 Delfia Fluorometer.

Beta amyloid 1-40, which had been aggregated as described above,produced fluorescence readings some 30 to 50 fold greater thanbackground. This increase in fluorescence was prevented when suitableinhibitors were included in the incubation. Peptide which had not beenpreincubated gave fluorescence readings only 2 to 3 times background.Thus, the increase on incubation is attributable to the detection ofaggregated peptide.

Determination of the Inhibition of the Formation of Toxic Aggregates ofBeta-Amyloid 1-40 Peptide

Beta-amyloid (1-40) peptide from Bachem UK was dissolved in 0.1% aceticacid at 2 mg/ml and further diluted to 55 ug/ml in phosphate bufferedsaline (Sigma P4417) containing 0.02% Tween 20 (PBS-Tween). Candidateinhibitors were dissolved in DMSO at 10 mg/ml and further diluted inPBS-Tween. For each candidate inhibitor, 45 ul of 55 ug/ml peptidesolution was incubated with 5 ul of appropriately diluted inhibitorovernight at 37° C. in Linbro Titertek EIA II shallow well plates (ICN,EIA II Microplates, cat no. 76-181-04). Plates were sealed with DynatechLabs (cat # 001-010 3501) plate sealers.

MTT (3(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide—Sigma)is a metabolic dye taken up by the mitochondria of viable cells andmetabolised, yielding a blue formazan crystalline product. This productcan by solubilised and the optical density of the blue solutiongenerated is proportional to the mitochondrial activity (viability) ofthe cells.

For the assessment of toxicity, IMR32 human neuroblastoma cells (ECACC,Porton Down, UK) were plated at 6×10⁴ cells/cm² in a 96 well microtitreplate (Nunc) in a volume of 100 ul growth medium (DMEM:Hams F12 1:1) perwell and incubated for 2 h (CO2 incubator, 37° C.). Incubatedbeta-amyloid 140 solutions containing candidate inhibitors were dilutedin growth medium to produce final (in contact with cells) beta-amyloid140 concentrations of 0.1 to 10 ng/ml, and added to the IMR32 cells.Vehicles are included in every assay. Plates were incubated overnight(CO2 incubator, 37° C.). To each well was then added 50 ul of MTTsolution (5 mg/ml in DMEM:F12/0.4% DMSO) added to each well and plateswere incubated for a further 4 hours (CO2 incubator, 37° C.). Medium wasthen aspirated and formazan product dissolved by addition of 200 ul ofDMSO and 25 ul of Sorensen's glycine buffer (0.1M glycine, 0.1M NaCl, pH10.5 with 0.1M NaOH). Plates were read at 590 nm and inhibition oftoxicity assessed as the difference in OD reading between cells in thepresence and absence of candidate inhibitors.

RESULTS

1) Immunoassay Results

Beta-amyloid 1-40 (50 ug/ml) was incubated, as described, withcarvedilol or analogues. Aggregated peptide content of incubates wasdetermined by immunoassay and inhibition determined as the decrease inthe maximally observed fluorescence reading.

2) Inhibition of Toxic Aggregate Formation in IMR32 Cells

In the example below, 50 ug/ml beta-amyloid 1-40 was incubated overnightwith 50 ug/ml carvedilol (or vehicle). The sample was then diluted ingrowth medium and cells challenged with 0 to 10 ng/ml beta-amyloid 1-40.In the absence of carvedilol, beta-amyloid 1-40 produced aconcentration-dependent decrease in MTT reduction over the peptide rangetested. The inclusion of carvedilol during the aggregation step resultedin a marked shift to the right in the concentration-response curve, suchthat no decrease in MTT reduction was observed at 0.1 to 1 ng/ml ofpeptide.

Results:

The foregoing are illustrative of the use of the compounds of thisinvention. This invention, however, is not limited to the preciseembodiments described herein, but encompasses all modifications withinthe scope of the claims which follow.

What is claimed is:
 1. A method for treating amyloid diseases whichcomprises administering to a mammal in need thereof an effective amountof a compound which is a dual non-selective β-adrenoceptor andα₁-adrenoceptor antagonist.
 2. The method according to claim 1 whereinthe compound is a compound of Formula I:

wherein: R₇-R₁₃ are independently —H or —OH; and A is H, —OH, or amoiety of Formula II:

 wherein: R₁ is hydrogen, lower alkanoyl of up to 6 carbon atoms oraroyl selected from benzoyl and naphthoyl; R₂ is hydrogen, lower alkylof up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyland phenylpropyl; R₃ is hydrogen or lower alkyl of up to 6 carbon atoms;R₄ is hydrogen or lower alkyl of up to 6 carbon atoms, or when X isoxygen, R₄ together with R₅ can represent —CH₂—O—; X is a valency bond,—CH₂, oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyland tetrahydronaphthyl; R₅ and R₆ are individually selected fromhydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6carbon atoms, a —CONH₂— group, lower alkoxy of up to 6 carbon atoms,benzyloxy, lower alkylthio of up to 6 carbon atoms, lower alkysulphinylof up to 6 carbon atoms and lower alkylsulphonyl of up to 6 carbonatoms; or R₅ and R₆ together represent methylenedioxy; or apharmaceutically acceptable salt thereof.
 3. The method according toclaim 1 wherein the compound is a compound of Formula III:

wherein: R₁ is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroylselected from benzoyl and naphthoyl; R₂ is hydrogen, lower alkyl of upto 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl andphenylpropyl; R₃ is hydrogen or lower alkyl of up to 6 carbon atoms; R₄is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen,R₄ together with R₅ can represent —CH₂—O—; X is a valency bond, —CH₂,oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyl andtetrahydronaphthyl; R₅ and R₆ are individually selected from hydrogen,fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbonatoms, a —CONH₂— group, lower alkoxy of up to 6 carbon atoms, benzyloxy,lower alkylthio of up to 6 carbon atoms, lower alkysulphinyl of up to 6carbon atoms and lower alkylsulphonyl of up to 6 carbon atoms; or or apharmaceutically acceptable salt thereof.
 4. The method according toclaim 1 wherein the compound is carvedilol.
 5. A method for treatingAlzheimer's disease which comprises administering to a mammal in needthereof an effective amount of a compound which is a dual non-selectiveβ-adrenoceptor and α₁-adrenoceptor antagonist.
 6. The method accordingto claim 5 wherein the compound is a compound of Formula I:

wherein: R₇-R₁₃ are independently —H or —OH; and A is H, —OH, or amoiety of Formula II:

 wherein: R₁ is hydrogen, lower alkanoyl of up to 6 carbon atoms oraroyl selected from benzoyl and naphthoyl; R₂ is hydrogen, lower alkylof up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyland phenylpropyl; R₃ is hydrogen or lower alkyl of up to 6 carbon atoms;R₄ is hydrogen or lower alkyl of up to 6 carbon atoms, or when X isoxygen, R₄ together with R₅ can represent —CH₂—O—; X is a valency bond,—CH₂, oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyland tetrahydronaphthyl; R₅ and R₆ are individually selected fromhydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6carbon atoms, a —CONH₂— group, lower alkoxy of up to 6 carbon atoms,benzyloxy, lower alkylthio of up to 6 carbon atoms, lower alkysulphinylof up to 6 carbon atoms and lower alkylsulphonyl of up to 6 carbonatoms; or R₅ and R₆ together represent methylenedioxy; or apharmaceutically acceptable salt thereof.
 7. The method according toclaim 5 wherein the compound is a compound of Formula III:

wherein: R₁ is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroylselected from benzoyl and naphthoyl; R₂ is hydrogen, lower alkyl of upto 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl andphenylpropyl; R₃ is hydrogen or lower alkyl of up to 6 carbon atoms; R₄is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen,R₄ together with R₅ can represent —CH₂—O—; X is a valency bond, —CH₂,oxygen or sulfur; Ar is selected from phenyl, naphthyl, indanyl andtetrahydronaphthyl; R₅ and R₆ are individually selected from hydrogen,fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbonatoms, a —CONH₂— group, lower alkoxy of up to 6 carbon atoms, benzyloxy,lower alkylthio of up to 6 carbon atoms, lower alkysulphinyl of up to 6carbon atoms and lower alkylsulphonyl of up to 6 carbon atoms; or or apharmaceutically acceptable salt thereof.
 8. The method according toclaim 5 wherein the compound is carvedilol.
 9. A method for treatingAlzheimer's disease which comprises administering stepwise or inphysical combination a compound of Formula I as defined in claim 6 and acognition enhancer.
 10. The method according to claim 9 wherein thecompound of Formula I is carvedilol.
 11. The method according to claim 9wherein the cognition enhancer is Memric.